AU2005287458A1 - Novel phthalazinone derivatives, as Aurora-a kinase inhibitors - Google Patents

Info

Publication number

AU2005287458A1

AU2005287458A1 AU2005287458A AU2005287458A AU2005287458A1 AU 2005287458 A1 AU2005287458 A1 AU 2005287458A1 AU 2005287458 A AU2005287458 A AU 2005287458A AU 2005287458 A AU2005287458 A AU 2005287458A AU 2005287458 A1 AU2005287458 A1 AU 2005287458A1

Authority

AU

Australia

Prior art keywords

methyl

alkyl

pyrazol

ylamino

phthalazin

Prior art date

2004-09-24

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical class C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 title claims description 65
• 108090000461 Aurora Kinase A Proteins 0.000 title description 7
• 102000004000 Aurora Kinase A Human genes 0.000 title description 5
• 229940043355 kinase inhibitor Drugs 0.000 title description 4
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 4
• 229910052739 hydrogen Inorganic materials 0.000 claims description 448
• 150000001875 compounds Chemical class 0.000 claims description 395
• 239000001257 hydrogen Substances 0.000 claims description 370
• 125000000217 alkyl group Chemical group 0.000 claims description 300
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 245
• 229910052736 halogen Inorganic materials 0.000 claims description 211
• 150000002367 halogens Chemical class 0.000 claims description 210
• 238000000034 method Methods 0.000 claims description 181
• 125000002947 alkylene group Chemical group 0.000 claims description 132
• -1 1,3-Dihydro-isobenzofuranyl Chemical group 0.000 claims description 118
• 125000003545 alkoxy group Chemical group 0.000 claims description 92
• 150000002431 hydrogen Chemical class 0.000 claims description 86
• 125000004414 alkyl thio group Chemical group 0.000 claims description 49
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 35
• 239000011541 reaction mixture Substances 0.000 claims description 34
• 230000001404 mediated effect Effects 0.000 claims description 26
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
• 125000001072 heteroaryl group Chemical group 0.000 claims description 24
• 150000003839 salts Chemical class 0.000 claims description 22
• 125000003118 aryl group Chemical group 0.000 claims description 20
• 230000008569 process Effects 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 18
• 125000000623 heterocyclic group Chemical group 0.000 claims description 15
• 238000004519 manufacturing process Methods 0.000 claims description 14
• 206010028980 Neoplasm Diseases 0.000 claims description 13
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
• 201000011510 cancer Diseases 0.000 claims description 11
• 125000003342 alkenyl group Chemical group 0.000 claims description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
• 201000010099 disease Diseases 0.000 claims description 9
• 125000001624 naphthyl group Chemical group 0.000 claims description 8
• DSDIWWSXOOXFSI-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-phenylphthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC=CC=3)N=2)=N1 DSDIWWSXOOXFSI-UHFFFAOYSA-N 0.000 claims description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
• RADYPHHNLDAXRN-UHFFFAOYSA-N 2-(4-methylphenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(C)=CC=3)N=2)=N1 RADYPHHNLDAXRN-UHFFFAOYSA-N 0.000 claims description 6
• 239000004480 active ingredient Substances 0.000 claims description 6
• 239000002671 adjuvant Substances 0.000 claims description 6
• YYPUQHOGGPATGQ-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-7-morpholin-4-yl-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC=C(N3CCOCC3)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 YYPUQHOGGPATGQ-UHFFFAOYSA-N 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• DFYXAPVQNGLJHI-UHFFFAOYSA-N 2-(4-chlorophenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(Cl)=CC=3)N=2)=N1 DFYXAPVQNGLJHI-UHFFFAOYSA-N 0.000 claims description 4
• PPOHPGMKFGMFKE-UHFFFAOYSA-N 2-benzyl-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(CC=3C=CC=CC=3)N=2)=N1 PPOHPGMKFGMFKE-UHFFFAOYSA-N 0.000 claims description 4
• SFPSMNFXHNJPKC-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-7-methylsulfanyl-2-propan-2-ylphthalazin-1-one Chemical compound N=1N(C(C)C)C(=O)C2=CC(SC)=CC=C2C=1NC=1C=C(C)NN=1 SFPSMNFXHNJPKC-UHFFFAOYSA-N 0.000 claims description 4
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 4
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 4
• SNLGNBKBVNOLQN-UHFFFAOYSA-N 2-(2-methylpropyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound C12=CC=CC=C2C(=O)N(CC(C)C)N=C1NC=1C=C(C)NN=1 SNLGNBKBVNOLQN-UHFFFAOYSA-N 0.000 claims description 3
• AIHXCSFEMCZERD-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(=CC=3)C(C)(C)C)N=2)=N1 AIHXCSFEMCZERD-UHFFFAOYSA-N 0.000 claims description 3
• JFPKFCDTLPRIHM-UHFFFAOYSA-N 2-methyl-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C)N=2)=N1 JFPKFCDTLPRIHM-UHFFFAOYSA-N 0.000 claims description 3
• RWGFZZRNLKELRN-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC=CC=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 RWGFZZRNLKELRN-UHFFFAOYSA-N 0.000 claims description 3
• GCINOQHISQCPLX-UHFFFAOYSA-N 6-(hydroxymethyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC(CO)=CC=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 GCINOQHISQCPLX-UHFFFAOYSA-N 0.000 claims description 3
• BYVGSHITSNINHB-UHFFFAOYSA-N 7-methoxy-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound N=1N(C(C)C)C(=O)C2=CC(OC)=CC=C2C=1NC=1C=C(C)NN=1 BYVGSHITSNINHB-UHFFFAOYSA-N 0.000 claims description 3
• 230000004913 activation Effects 0.000 claims description 3
• XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 claims description 3
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• UPQYIBBMKCUDOH-UHFFFAOYSA-N 1-[(5-methyl-1h-pyrazol-3-yl)amino]-4-oxo-3-propan-2-ylphthalazine-6-carboxylic acid Chemical compound C12=CC=C(C(O)=O)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 UPQYIBBMKCUDOH-UHFFFAOYSA-N 0.000 claims description 2
• KXDXRUIDSHLCLJ-UHFFFAOYSA-N 1-[(5-methyl-1h-pyrazol-3-yl)amino]-4-oxo-n,3-di(propan-2-yl)phthalazine-6-carboxamide Chemical compound N=1N(C(C)C)C(=O)C2=CC(C(=O)NC(C)C)=CC=C2C=1NC=1C=C(C)NN=1 KXDXRUIDSHLCLJ-UHFFFAOYSA-N 0.000 claims description 2
• IDBHVMOAVKHXLQ-UHFFFAOYSA-N 2-(1-methoxypropan-2-yl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound C12=CC=CC=C2C(=O)N(C(C)COC)N=C1NC1=CC(C)=NN1 IDBHVMOAVKHXLQ-UHFFFAOYSA-N 0.000 claims description 2
• LFDTXCUWIRDLIH-UHFFFAOYSA-N 2-(2-hydroxy-2-phenylethyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(CC(O)C=3C=CC=CC=3)N=2)=N1 LFDTXCUWIRDLIH-UHFFFAOYSA-N 0.000 claims description 2
• OZZHXALBVFHCTL-UHFFFAOYSA-N 2-(4-aminophenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(N)=CC=3)N=2)=N1 OZZHXALBVFHCTL-UHFFFAOYSA-N 0.000 claims description 2
• YCBANIRJITUGBB-UHFFFAOYSA-N 2-(4-anilinophenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(NC=4C=CC=CC=4)=CC=3)N=2)=N1 YCBANIRJITUGBB-UHFFFAOYSA-N 0.000 claims description 2
• UCFRRVHNWQGQQL-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-4-[(5-cyclopropyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound C1=CC(C(C)(C)C)=CC=C1N1C(=O)C2=CC=CC=C2C(NC2=NNC(=C2)C2CC2)=N1 UCFRRVHNWQGQQL-UHFFFAOYSA-N 0.000 claims description 2
• WZXXOCWIKFBCCV-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]-6-nitrophthalazin-1-one Chemical compound N1N=C(C)C=C1NC(C1=CC(=CC=C1C1=O)[N+]([O-])=O)=NN1C1=CC=C(C(C)(C)C)C=C1 WZXXOCWIKFBCCV-UHFFFAOYSA-N 0.000 claims description 2
• BAQTWRIYOIQOLT-UHFFFAOYSA-N 2-[2-(3-methoxyphenyl)-2-oxoethyl]-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound COC1=CC=CC(C(=O)CN2C(C3=CC=CC=C3C(NC3=NNC(C)=C3)=N2)=O)=C1 BAQTWRIYOIQOLT-UHFFFAOYSA-N 0.000 claims description 2
• KORPJXOHLXUGLD-UHFFFAOYSA-N 2-[4-(2-methylphenyl)phenyl]-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(=CC=3)C=3C(=CC=CC=3)C)N=2)=N1 KORPJXOHLXUGLD-UHFFFAOYSA-N 0.000 claims description 2
• HQKWIUMWENHMAK-UHFFFAOYSA-N 2-[4-(benzenesulfinyl)phenyl]-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(=CC=3)S(=O)C=3C=CC=CC=3)N=2)=N1 HQKWIUMWENHMAK-UHFFFAOYSA-N 0.000 claims description 2
• CCFDAIDGRFLIMY-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-(4-morpholin-4-ylphenyl)phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(=CC=3)N3CCOCC3)N=2)=N1 CCFDAIDGRFLIMY-UHFFFAOYSA-N 0.000 claims description 2
• XVFNPIXCCDMGHN-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-(4-pyrrolidin-1-ylphenyl)phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(=CC=3)N3CCCC3)N=2)=N1 XVFNPIXCCDMGHN-UHFFFAOYSA-N 0.000 claims description 2
• LFCPSKGFPCUNRQ-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-[(4-methylsulfonylphenyl)methyl]phthalazin-1-one Chemical compound N1N=C(C)C=C1NC(C1=CC=CC=C1C1=O)=NN1CC1=CC=C(S(C)(=O)=O)C=C1 LFCPSKGFPCUNRQ-UHFFFAOYSA-N 0.000 claims description 2
• GYEHAWHVTQCLGS-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-[2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(CC(=O)C=3C=CC(=CC=3)C(F)(F)F)N=2)=N1 GYEHAWHVTQCLGS-UHFFFAOYSA-N 0.000 claims description 2
• MODADWRACQIEMS-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-[4-(trifluoromethyl)phenyl]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(=CC=3)C(F)(F)F)N=2)=N1 MODADWRACQIEMS-UHFFFAOYSA-N 0.000 claims description 2
• ZYWAUCIAPLYMIZ-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-phenacylphthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(CC(=O)C=3C=CC=CC=3)N=2)=N1 ZYWAUCIAPLYMIZ-UHFFFAOYSA-N 0.000 claims description 2
• MCFZHKNVWQQTEZ-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-yl-7-pyrrolidin-1-ylphthalazin-1-one Chemical compound C12=CC=C(N3CCCC3)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 MCFZHKNVWQQTEZ-UHFFFAOYSA-N 0.000 claims description 2
• XGSLTRQNYXVCOZ-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-pyridin-4-ylphthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CN=CC=3)N=2)=N1 XGSLTRQNYXVCOZ-UHFFFAOYSA-N 0.000 claims description 2
• LRHCLHFWKMHUHB-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-7-(2-morpholin-4-ylethylamino)-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC=C(NCCN3CCOCC3)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 LRHCLHFWKMHUHB-UHFFFAOYSA-N 0.000 claims description 2
• OBZDHAOQBXMXPM-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-7-methylsulfonyl-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC=C(S(C)(=O)=O)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 OBZDHAOQBXMXPM-UHFFFAOYSA-N 0.000 claims description 2
• KEYBVRYSELNSNO-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-7-piperidin-1-yl-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC=C(N3CCCCC3)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 KEYBVRYSELNSNO-UHFFFAOYSA-N 0.000 claims description 2
• BQTSRUOQPLYEOH-UHFFFAOYSA-N 6-amino-2-(4-tert-butylphenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1N=C(C)C=C1NC(C1=CC(N)=CC=C1C1=O)=NN1C1=CC=C(C(C)(C)C)C=C1 BQTSRUOQPLYEOH-UHFFFAOYSA-N 0.000 claims description 2
• AVFWYYLCCVCXAJ-UHFFFAOYSA-N 6-bromo-2-(4-tert-butylphenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1N=C(C)C=C1NC(C1=CC(Br)=CC=C1C1=O)=NN1C1=CC=C(C(C)(C)C)C=C1 AVFWYYLCCVCXAJ-UHFFFAOYSA-N 0.000 claims description 2
• YOEHKEYZYJAGQB-UHFFFAOYSA-N 7-(difluoromethoxy)-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC=C(OC(F)F)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 YOEHKEYZYJAGQB-UHFFFAOYSA-N 0.000 claims description 2
• MNOYVFBSAHLRIP-UHFFFAOYSA-N 7-(dimethylamino)-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC=C(N(C)C)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 MNOYVFBSAHLRIP-UHFFFAOYSA-N 0.000 claims description 2
• LHFMCPATRIPRDO-UHFFFAOYSA-N 7-(hydroxymethyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC=C(CO)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 LHFMCPATRIPRDO-UHFFFAOYSA-N 0.000 claims description 2
• QFLJUVVELFERAA-UHFFFAOYSA-N 7-(methylamino)-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound N=1N(C(C)C)C(=O)C2=CC(NC)=CC=C2C=1NC=1C=C(C)NN=1 QFLJUVVELFERAA-UHFFFAOYSA-N 0.000 claims description 2
• DSSJZXRCQUUWCH-UHFFFAOYSA-N 7-amino-2-(4-tert-butylphenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1N=C(C)C=C1NC(C1=CC=C(N)C=C1C1=O)=NN1C1=CC=C(C(C)(C)C)C=C1 DSSJZXRCQUUWCH-UHFFFAOYSA-N 0.000 claims description 2
• DCYWTIDCLZTFNS-UHFFFAOYSA-N chembl447887 Chemical compound C12=CC=C(O)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 DCYWTIDCLZTFNS-UHFFFAOYSA-N 0.000 claims description 2
• FLSHMLNYFPRRNE-UHFFFAOYSA-N ethyl n-[4-[4-[(5-methyl-1h-pyrazol-3-yl)amino]-1-oxophthalazin-2-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OCC)=CC=C1N1C(=O)C2=CC=CC=C2C(NC2=NNC(C)=C2)=N1 FLSHMLNYFPRRNE-UHFFFAOYSA-N 0.000 claims description 2
• AJTMNHRQOKLKGR-UHFFFAOYSA-N ethyl n-methyl-n-[1-[(5-methyl-1h-pyrazol-3-yl)amino]-4-oxo-3-propan-2-ylphthalazin-6-yl]carbamate Chemical compound N=1N(C(C)C)C(=O)C2=CC(N(C)C(=O)OCC)=CC=C2C=1NC=1C=C(C)NN=1 AJTMNHRQOKLKGR-UHFFFAOYSA-N 0.000 claims description 2
• ZJRGLONAKYESMA-UHFFFAOYSA-N methyl 1-[(5-methyl-1h-pyrazol-3-yl)amino]-4-oxo-3-propan-2-ylphthalazine-6-carboxylate Chemical compound N=1N(C(C)C)C(=O)C2=CC(C(=O)OC)=CC=C2C=1NC=1C=C(C)NN=1 ZJRGLONAKYESMA-UHFFFAOYSA-N 0.000 claims description 2
• FJRMWZGNPCFACR-UHFFFAOYSA-N n-[3-(4-tert-butylphenyl)-1-[(5-methyl-1h-pyrazol-3-yl)amino]-4-oxophthalazin-6-yl]formamide Chemical compound N1N=C(C)C=C1NC(C1=CC=C(NC=O)C=C1C1=O)=NN1C1=CC=C(C(C)(C)C)C=C1 FJRMWZGNPCFACR-UHFFFAOYSA-N 0.000 claims description 2
• JRBMAZMBQUFLGS-UHFFFAOYSA-N n-[4-[[4-[(5-methyl-1h-pyrazol-3-yl)amino]-1-oxophthalazin-2-yl]methyl]phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1CN1C(=O)C2=CC=CC=C2C(NC2=NNC(C)=C2)=N1 JRBMAZMBQUFLGS-UHFFFAOYSA-N 0.000 claims description 2
• WJBGUZCJZYKKTR-UHFFFAOYSA-N n-methoxy-1-[(5-methyl-1h-pyrazol-3-yl)amino]-4-oxo-3-propan-2-ylphthalazine-6-carboxamide Chemical compound N=1N(C(C)C)C(=O)C2=CC(C(=O)NOC)=CC=C2C=1NC=1C=C(C)NN=1 WJBGUZCJZYKKTR-UHFFFAOYSA-N 0.000 claims description 2
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
• VRODJFLMTSTPKK-UHFFFAOYSA-N 2,2-dimethyl-n-[4-[4-[(5-methyl-1h-pyrazol-3-yl)amino]-1-oxophthalazin-2-yl]phenyl]propanamide Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(NC(=O)C(C)(C)C)=CC=3)N=2)=N1 VRODJFLMTSTPKK-UHFFFAOYSA-N 0.000 claims 1
• SYVLQSPSGXPACG-UHFFFAOYSA-N 2-(3-methylphenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=C(C)C=CC=3)N=2)=N1 SYVLQSPSGXPACG-UHFFFAOYSA-N 0.000 claims 1
• HGBXEDXLZADGJI-UHFFFAOYSA-N 2-(3-tert-butylphenyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=C(C=CC=3)C(C)(C)C)N=2)=N1 HGBXEDXLZADGJI-UHFFFAOYSA-N 0.000 claims 1
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• AWTKGJLXHNEPML-UHFFFAOYSA-N 2-(4-tert-butylcyclohexyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C3CCC(CC3)C(C)(C)C)N=2)=N1 AWTKGJLXHNEPML-UHFFFAOYSA-N 0.000 claims 1
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• SVTBFGDAWVMFBQ-UHFFFAOYSA-N 2-[(2,5-difluorophenyl)methyl]-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(CC=3C(=CC=C(F)C=3)F)N=2)=N1 SVTBFGDAWVMFBQ-UHFFFAOYSA-N 0.000 claims 1
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• FULBCSTUNJDMJE-UHFFFAOYSA-N 2-[(3,5-difluorophenyl)methyl]-4-[(5-methyl-1h-pyrazol-3-yl)amino]phthalazin-1-one Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(CC=3C=C(F)C=C(F)C=3)N=2)=N1 FULBCSTUNJDMJE-UHFFFAOYSA-N 0.000 claims 1
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• IDULIKJYOSIWKL-UHFFFAOYSA-N 4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-(4-piperidin-1-ylphenyl)phthalazin-1-one Chemical compound N1N=C(C)C=C1NC(C1=CC=CC=C1C1=O)=NN1C1=CC=C(N2CCCCC2)C=C1 IDULIKJYOSIWKL-UHFFFAOYSA-N 0.000 claims 1
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• VUKXSLPATWDPEZ-UHFFFAOYSA-N 6-(dimethylamino)-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC(N(C)C)=CC=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 VUKXSLPATWDPEZ-UHFFFAOYSA-N 0.000 claims 1
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• NAWJCEJEKZAVIT-UHFFFAOYSA-N 6-methoxy-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound C=1C(OC)=CC=C(C(N(C(C)C)N=2)=O)C=1C=2NC=1C=C(C)NN=1 NAWJCEJEKZAVIT-UHFFFAOYSA-N 0.000 claims 1
• OWOZPEZKOZDVPB-UHFFFAOYSA-N 7-(methoxymethyl)-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound N=1N(C(C)C)C(=O)C2=CC(COC)=CC=C2C=1NC=1C=C(C)NN=1 OWOZPEZKOZDVPB-UHFFFAOYSA-N 0.000 claims 1
• RKLLRMTXOSDKOA-UHFFFAOYSA-N 7-[(4-fluorophenyl)methyl-methylamino]-4-[(5-methyl-1h-pyrazol-3-yl)amino]-2-propan-2-ylphthalazin-1-one Chemical compound C12=CC=C(N(C)CC=3C=CC(F)=CC=3)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 RKLLRMTXOSDKOA-UHFFFAOYSA-N 0.000 claims 1
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• FNVSPRVAHACXGP-UHFFFAOYSA-N cyclopropylmethyl phthalazine-6-carboxylate Chemical compound C1(CC1)COC(=O)C=1C=C2C=NN=CC2=CC=1 FNVSPRVAHACXGP-UHFFFAOYSA-N 0.000 claims 1
• WTFVTHCZKRHGJC-UHFFFAOYSA-N n-[1-[(5-methyl-1h-pyrazol-3-yl)amino]-4-oxo-3-propan-2-ylphthalazin-6-yl]methanesulfonamide Chemical compound C12=CC=C(NS(C)(=O)=O)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 WTFVTHCZKRHGJC-UHFFFAOYSA-N 0.000 claims 1
• WZHGJYUXVLRNHJ-UHFFFAOYSA-N n-[4-[4-[(5-methyl-1h-pyrazol-3-yl)amino]-1-oxophthalazin-2-yl]phenyl]benzamide Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(NC(=O)C=4C=CC=CC=4)=CC=3)N=2)=N1 WZHGJYUXVLRNHJ-UHFFFAOYSA-N 0.000 claims 1
• VNGPRQJPXRLXIR-UHFFFAOYSA-N n-[4-[4-[(5-methyl-1h-pyrazol-3-yl)amino]-1-oxophthalazin-2-yl]phenyl]methanesulfonamide Chemical compound N1C(C)=CC(NC=2C3=CC=CC=C3C(=O)N(C=3C=CC(NS(C)(=O)=O)=CC=3)N=2)=N1 VNGPRQJPXRLXIR-UHFFFAOYSA-N 0.000 claims 1
• YEGCYVBYUURCCX-UHFFFAOYSA-N n-ethyl-n-[4-[4-[(5-methyl-1h-pyrazol-3-yl)amino]-1-oxophthalazin-2-yl]phenyl]acetamide Chemical compound C1=CC(N(C(C)=O)CC)=CC=C1N1C(=O)C2=CC=CC=C2C(NC2=NNC(C)=C2)=N1 YEGCYVBYUURCCX-UHFFFAOYSA-N 0.000 claims 1
• XTKVLDIXEWLAMG-UHFFFAOYSA-N n-methyl-n-[1-[(5-methyl-1h-pyrazol-3-yl)amino]-4-oxo-3-propan-2-ylphthalazin-6-yl]acetamide Chemical compound C12=CC=C(N(C)C(C)=O)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 XTKVLDIXEWLAMG-UHFFFAOYSA-N 0.000 claims 1
• CRCMEQXEHQVWBN-UHFFFAOYSA-N n-methyl-n-[1-[(5-methyl-1h-pyrazol-3-yl)amino]-4-oxo-3-propan-2-ylphthalazin-6-yl]methanesulfonamide Chemical compound C12=CC=C(N(C)S(C)(=O)=O)C=C2C(=O)N(C(C)C)N=C1NC=1C=C(C)NN=1 CRCMEQXEHQVWBN-UHFFFAOYSA-N 0.000 claims 1
• HSDHAMAXKIWRIR-UHFFFAOYSA-N phthalazine-6-carboxamide Chemical compound C1=NN=CC2=CC=C(C=C12)C(=O)N HSDHAMAXKIWRIR-UHFFFAOYSA-N 0.000 claims 1
• FINVTRLVIAQTLW-UHFFFAOYSA-N propan-2-yl n-[4-[4-[(5-methyl-1h-pyrazol-3-yl)amino]-1-oxophthalazin-2-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC(C)C)=CC=C1N1C(=O)C2=CC=CC=C2C(NC2=NNC(C)=C2)=N1 FINVTRLVIAQTLW-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 193
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 168
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 168
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 159
• 238000006243 chemical reaction Methods 0.000 description 126
• 239000000203 mixture Substances 0.000 description 120
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• 239000002904 solvent Substances 0.000 description 106
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 93
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 85
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 85
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 84
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 76
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
• 239000003153 chemical reaction reagent Substances 0.000 description 66
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• 239000002585 base Substances 0.000 description 62
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• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 58
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 51
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• 230000015572 biosynthetic process Effects 0.000 description 47
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• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 42
• 238000004949 mass spectrometry Methods 0.000 description 42
• 238000005160 1H NMR spectroscopy Methods 0.000 description 38
• JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 36
• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 34
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 34
• 238000003786 synthesis reaction Methods 0.000 description 34
• 229960000583 acetic acid Drugs 0.000 description 32
• 239000007787 solid Substances 0.000 description 32
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 32
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• 229910052763 palladium Inorganic materials 0.000 description 29
• 229910000027 potassium carbonate Inorganic materials 0.000 description 29
• 235000011181 potassium carbonates Nutrition 0.000 description 29
• 239000000243 solution Substances 0.000 description 29
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 28
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 26
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
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• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
• 241000894007 species Species 0.000 description 24
• 230000029936 alkylation Effects 0.000 description 23
• 238000005804 alkylation reaction Methods 0.000 description 23
• 239000000010 aprotic solvent Substances 0.000 description 23
• 230000009897 systematic effect Effects 0.000 description 23
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 22
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• 125000004356 hydroxy functional group Chemical group O* 0.000 description 21
• WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 20
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
• CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 18
• 238000003556 assay Methods 0.000 description 18
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 18
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
• 150000001298 alcohols Chemical class 0.000 description 17
• 238000005576 amination reaction Methods 0.000 description 17
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• INLLPKCGLOXCIV-UHFFFAOYSA-N bromoethene Chemical compound BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 description 17
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 17
• 229910000024 caesium carbonate Inorganic materials 0.000 description 17
• 239000003446 ligand Substances 0.000 description 17
• PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 17
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 17
• 229910000073 phosphorus hydride Inorganic materials 0.000 description 17
• IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 17
• 239000000725 suspension Substances 0.000 description 17
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 16
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• YSZIOXAEADAJLX-UHFFFAOYSA-N phthalazine-1,4-dione Chemical class C1=CC=C2C(=O)N=NC(=O)C2=C1 YSZIOXAEADAJLX-UHFFFAOYSA-N 0.000 description 16
• 239000007858 starting material Substances 0.000 description 16
• DHXVJJHOVGTNDK-UHFFFAOYSA-N 4-bromo-2h-phthalazin-1-one Chemical class C1=CC=C2C(Br)=NNC(=O)C2=C1 DHXVJJHOVGTNDK-UHFFFAOYSA-N 0.000 description 15
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
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• 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
• 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
• GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
• FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
• 231100000419 toxicity Toxicity 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• 229910052723 transition metal Inorganic materials 0.000 description 1
• 150000003624 transition metals Chemical class 0.000 description 1
• 230000014616 translation Effects 0.000 description 1
• 125000004306 triazinyl group Chemical group 0.000 description 1
• 125000006387 trifluoromethyl pyridyl group Chemical group 0.000 description 1
• 230000001960 triggered effect Effects 0.000 description 1
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
• 230000004614 tumor growth Effects 0.000 description 1
• 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
• 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
• 229920002554 vinyl polymer Polymers 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• 238000005550 wet granulation Methods 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1
• 238000010626 work up procedure Methods 0.000 description 1
• 229910052727 yttrium Inorganic materials 0.000 description 1